Impact of nonsteroidal anti-inflammatory drugs on efficacy of anti-PD-1 therapy for primary liver cancer / 南方医科大学学报

OBJECTIVE@#To assess the impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on clinical outcomes of patients receiving anti-PD-1 immunotherapy for hepatocellular carcinoma.@*METHODS@#We conducted a retrospective study among 215 patients with primary liver cancer receiving immunotherapy between June, 2018 and October, 2020. The patients with balanced baseline characteristics were selected based on propensity matching scores, and among them 33 patients who used NSAIDs were matched at the ratio of 1∶3 with 78 patients who did not use NSAIDs. We compared the overall survival (OS), progression-free survival (PFS), and disease control rate (DCR) between the two groups.@*RESULTS@#There was no significant difference in OS between the patients using NSAIDs (29.7%) and those who did not use NSAIDs (70.2%). Univariate and multivariate analyses did not show an a correlation of NSAIDs use with DCR (univariate analysis: OR=0.602, 95% CI: 0.299-1.213, P=0.156; multivariate analysis: OR=0.693, 95% CI: 0.330-1.458, P=0.334), PFS (univariate analysis: HR=1.230, 95% CI: 0.789-1.916, P=0.361; multivariate analysis: HR=1.151, 95% CI: 0.732-1.810, P=9.544), or OS (univariate analysis: HR=0.552, 95% CI: 0.208-1.463, P=0.232; multivariate analysis: HR=1.085, 95% CI: 0.685-1.717, P=0.729).@*CONCLUSION@#Our results show no favorable effect of NSAIDs on the efficacy of immunotherapy in patients with advanced primary liver cancer, but this finding still needs to be verified by future prospective studies of large cohorts.

Immunotherapy for microsatellite-instability-high advanced colorectal cancer / 中华胃肠外科杂志

Microsatellite instability-high (MSI-H) colorectal cancer accounts for approximately 10%-15% of all colorectal cancer patients, while in metastatic diseases the MSI-H population accounts for only 5% of patients. Previous studies have shown that early-stage MSI-H colorectal cancer patients have a good prognosis, but those with advanced disease have a poor prognosis and are not sensitive to chemotherapy. The advent of PD-1 antibodies has significantly improved the prognosis and changed treatment landscape in this population, not only achieving good outcomes in late-line therapy, but also significantly outperforming traditional chemotherapy combined with targeted therapy in first-line therapy. How to overcome primary and secondary drug resistance is a key issue in improving the outcome of MSI-H metastatic colorectal cancer, and commonly used approaches include changing chemotherapy regimens, combining with other immunotherapies, combining with anti-angiogenesis, and local treatments (surgery, radiotherapy, or interventional therapy). It is worth noting that immunotherapy has certain lifelong or even lethal toxicity, and the indications for neoadjuvant immunotherapy must be evaluated with caution. Neoadjuvant immunotherapy in MSI-H advantaged population can achieve high rates of pathological complete remission (pCR) and clinical complete remission (cCR). Therefore, for MSI-H patients with a strong intention to preserve anal sphincter and a strict evaluation of cCR after neoadjuvant immunotherapy, the Watch-and-Wait strategy offers an opportunity to preserve sphincter function and improve long-term survival quality in a subset of mid-to-low rectal cancers. Research on adjuvant immunotherapy in the field of colorectal cancer is also in full swing, and the results are worth waiting for.

Predictive model of curative effect of mite subcutaneous immunotherapy in 5-18 years of age patients with allergic asthma / 中华儿科杂志

Objective: To analyze the factors affecting the efficacy of mite subcutaneous immunotherapy (SCIT) in allergic asthma patients aged 5-18 years, and to find the best predictive model for the curative effect. Methods: The data of 688 patients aged 5-18 years with allergic asthma who completed more than 3 years of mite SCIT from December 2006 to November 2021 in the Department of Respiratory Medicine, Children's Hospital Affiliated to Nanjing Medical University were retrospectively analyzed. Male, results of skin prick test (SPT), age, daily medication score (DMS), visual analogue scale (VAS) score, and enrollment season were defined as independent variables. R language models, including Logistic regression model, random forest model and extreme gradient boosting (XGboost) model, were used to analyze the impact of these independent variables on the outcomes. The receiver operating characteristic curve was applied to compare the predictive ability of the models. Hypothesis testing of the area under curve (AUC) of the 3 models was performed using DeLong test. Results: There were 435 males and 253 females in the 688 patients. There were 349 patients aged 5-<8 years, 240 patients aged 8-<11 years, and 99 patients aged 11-18 years. SPT showed that 429 cases (62.4%) were only allergic to mite, and 259 cases (37.7%) were also allergic to other allergens. According to the efficacy after 3 years of SCIT, 351 cases (51.0%) discontinued the treatment and 337 cases (49.0%) required continued treatment. The DMS was 4 (3, 6) at initiation, 3 (2, 5) at 3 months, 3 (2, 5) at 4 months, 2 (1, 3) at 12 months, and 0 (0, 1) at 3 years of SCIT treatment. The VAS was 3.5 (2.5, 5.2) at initiation, 3.2 (2.2, 4.8) at 3 months, 2.6 (1.4, 4.1) at 4 months, 1.0 (0.6, 1.8) at 12 months, and 0.5 (0, 1.2) at 3 years of treatment. At 3, 4, and 12 months, the rate of decline in DMS was 0 (0, 20%), 16.7% (0, 33.3%), and 50.0% (31.0%, 75.0%), respectively; and the VAS decreased by 7.1% (3.2%,13.8%), 27.6% (16.7%,44.4%), and 70.2% (56.1%, 82.3%), respectively. Regarding the enrollment season, 99 cases were in spring, 230 cases in summer, 171 cases in autumn, and 188 cases in winter. The R language Logistic regression model found that DMS>3 points at 3 months (OR=-3.5, 95%CI:-4.3--2.7, P<0.01), male (OR=-1.7, 95%CI:-2.3--1.0), P<0.01), DMS decline rate>16.7% at 4 months (OR=-1.6, 95%CI:-2.3--0.8, P<0.01) and DMS decline rate>0 at 3 months (OR=-0.7, 95%CI:-1.3--0.2, P<0.05) had higher possibility of drug discontinuation; whereas, the decline rate of DMS at 12 months>50.0% (OR=0.7, 95%CI: 0.1-1.3, P<0.05), VAS at 12 months>1.0 points (OR=0.9, 95%CI: 0.3-1.6, P<0.05), and initial VAS<4.0 points (OR=1.0, 95%CI: 0.4-1.6, P<0.01) had lower possibility of drug discontinuation. Both the random forest model and the XGboost model showed that DMS>3 points at 3 months (mean decrease accuracy=30.9, importance=0.45) had the greatest impact on drug discontinuation. The AUC of the random forest model was the largest at 0.900, with an accuracy of 78.2% and a sensitivity of 84.5%. Logistic regression model had AUC of 0.891, accuracy of 80.0%, and sensitivity of 80.0%; XGboost model had AUC of 0.886, accuracy of 76.9%, and sensitivity of 84.5%. The AUC of the pairwise comparison model by DeLong test found that all three models could be used for the prediction of this data set (all P>0.05). Conclusions: The more drugs used to control the primary disease, and the more careful reduction of the control medicine after starting SCIT treatment, the more favorable it is to stop all drugs after 3 years. The random forest model is the best predictive model for the efficacy of mite SCIT in asthmatic children.

Progress of Neoadjuvant Immunotherapy for Non-small Cell Lung Cancer / 中国肺癌杂志

Neoadjuvant immunotherapy, including neoadjuvant single- or dual-drug immunotherapy or combined immunotherapy with chemotherapy or radiotherapy, has witnessed a rapid development in non-small cell lung cancer. Clinical trials exhibited the encouraging pathological responses and certain clinical benefits in selected patients, with tolerable toxicity. Nivolumab with chemotherapy has been approved by Food and Drug Administration (FDA) as the first immunotherapy-based treatment for non-small cell lung cancer in the neoadjuvant treatment setting. There is the need for further evaluation of long-term efficacy, side effects or surgical issues for neoadjuvant immunotherapy in non-small cell lung cancer.
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Clinical Progress in the Immunotherapy of Small Cell Lung Cancer / 中国肺癌杂志

Small cell lung cancer is a kind of malignant tumor with strong invasiveness and poor prognosis, and the classic therapeutic modality of the disease remains multidisciplinary and comprehensive treatment. Treatment options for small cell lung cancer have been stalled for a long time, and new opportunities have emerged in recent years due to the development and initial experience of immunotherapeutic drugs. Clinical trials of some selected immune checkpoint inhibitors have confirmed the efficacy and safety in small cell lung cancer. Based on the results of phase III clinical trials (Impower133 and CASPIAN), Atezolizumab or Durvalumab in combination with chemotherapy has been approved by the U.S. Food and Drug Administration for the first-line treatment of extensive-stage small cell lung cancer. Clinical trials involving immune checkpoint inhibitors are being actively carried out and provide different perspectives for the management of small cell lung cancer. This article aimed to review the clinical progress in immunotherapy of small cell lung cancer.
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A comprehensive profile of TCF1+ progenitor and TCF1- terminally exhausted PD-1+CD8+ T cells in head and neck squamous cell carcinoma: implications for prognosis and immunotherapy / 国际口腔科学杂志·英文版

The heterogeneity of exhausted T cells (Tex) is a critical determinant of immune checkpoint blockade therapy efficacy. However, few studies have explored exhausted T cell subpopulations in human cancers. In the present study, we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer (HNSCC) by multiplex immunohistochemistry (mIHC) to investigate two subsets of Tex, CD8+PD1+TCF1+ progenitor exhausted T cells (TCF1+Texprog) and CD8+PD1+TCF1- terminally exhausted T cells (TCF1-Texterm). Moreover, fresh tumor samples from 34 patients with HNSCC were examined by flow cytometry and immunohistochemistry to further investigate their properties and cytotoxic capabilities and their correlation with regulatory T cells (Tregs) in the tumor immune microenvironment (TIME). mIHC and flow cytometry analysis showed that TCF1-Texterm represented a greater proportion of CD8+PD1+Tex than TCF1+Texprog in most patients. TCF1+Texprog produced abundant TNFα, while TCF1-Texterm expressed higher levels of CD103, TIM-3, CTLA-4, and TIGIT. TCF1-Texterm exhibited a polyfunctional TNFα+GZMB+IFNγ+ phenotype; and were associated with better overall survival and recurrence-free survival. The results also indicated that larger proportions of TCF1-Texterm were accompanied by an increase in the proportion of Tregs. Therefore, it was concluded that TCF1-Texterm was the major CD8+PD1+Tex subset in the HNSCC TIME and that these cells favor patient survival. A high proportion of TCF1-Texterm was associated with greater Treg abundance.

Treatment Sequencing Strategies in Lung Cancer / 中国肺癌杂志

BACKGROUND@#The advances in the lung cancer screening methods and therapeutics, together with awareness towards deleterious habits, such as smoking, is increasing the overall survival with better quality of life for the patients. However, lung cancer is still one of the most common and fatal neoplasm with a high incidence and consequently burden to public health worldwide. Thus, based on guidelines and recent phases II and III clinical trials studies, this manuscript summarizes the current treatment sequencing strategies in lung cancer.@*METHODS@#A comprehensive search of related articles was performed focused on phases II and III clinical trials studies.@*RESULTS@#The lung cancer management should take into consideration the tumor characteristics, histology, molecular pathology and be discussed in a multidisciplinary team. Lung cancer treatment options comprises surgery whenever possible, radiotherapy associate with/or chemotherapy and immunotherapy as monotherapy, or combined with chemotherapy and best palliative care.@*CONCLUSIONS@#The screening predictability in more patients, smoking reduction, early diagnosis, better disease understanding and individualized, more effective and tolerable therapeutics are related to an increasing in overall survival and quality of life. In the near future improvement of personalized therapy in precision medicine is expected, enhancing new predictive biomarkers, optimal doses and optimal treatment sequencing as well as anti-cancer vaccines development.

Research Progress, Benefit Groups, Treatment Cycle and Efficacy Prediction of Neoadjuvant Immunotherapy for Non-small Cell Lung Cancer / 中国肺癌杂志

The emergence of immune checkpoint inhibitors (ICIs) has dramatically changed the therapeutic outlook for patients with non-small cell lung cancer (NSCLC). Preoperative neoadjuvant immunotherapy has been paid more and more attention as an effective and safe treatment. Neoadjuvant immune therapy, however, the relevant research started late, relatively few research results and mainly focused on the small sample size of phase I and II studies, treatment itself exists many places it is not clear, also in benefit population screening, the respect such as the choice of treatment and curative effect prediction has not yet reached broad consensus. This paper reviews the important studies and recent achievements related to neoadjuvant immunotherapy, aiming to comprehensively discuss the procedures and existing problems of this kind of therapy from three aspects of beneficiary groups, treatment cycle and efficacy prediction.
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Anti-PD-1 and anti-PD-l1 antibodies as immunotherapy against cancer: a structural perspective

ABSTRACT Programmed cell death protein 1 (PD-1) and its ligand, programmed death-ligand-1 (PD-L1), play key roles in the suppression of the cytotoxic activity of T cells. PD-L1 is overexpressed on various types of cancer cells, leading to immune evasion. In the past decade, therapeutic antibodies that target the PD-1/PD-L1 axis have been developed to inhibit the immune suppression triggered by these two proteins. At present, five antibodies (two anti-PD-1 and three anti-PD-L1) have received approval by regulatory agencies in the US and Europe. In this work, we aimed to review their clinical applications and adverse effects. Furthermore, using their reported crystal structures, we discuss the similarities and differences between the PD-1/PD-L1 interface and the epitopes that are recognized by the antibodies. Detailed analyses of the contact residues involved in the ligand-receptor and target-antibody interactions have shown partial overlap. Altogether, the data presented here demonstrate that: (1) in contrast to other therapeutic antibodies, anti-PD-1/PD-L1 has a wide range of clinical applications; (2) these targeted therapies are not exempt from adverse effects; and (3) the characterization of the structural domains that are recognized by the antibodies can guide the development of new PD-1- and PD-L1-blocking agents. (REV INVEST CLIN. 2021;73(1):8-16)

Peripheral Blood Inflammation Indicators as Predictive Indicators in Immunotherapy of Advanced Non-small Cell Lung Cancer / 中国肺癌杂志

BACKGROUND@#Lung cancer is the leading cause of cancer-related death, of which non-small cell lung cancer (NSCLC) is the most common type. Immune checkpoint inhibitors (ICIs) have now become one of the main treatments for advanced NSCLC. This paper retrospectively investigated the effect of peripheral blood inflammatory indexes on the efficacy of immunotherapy and survival of patients with advanced non-small cell lung cancer, in order to find strategies to guide immunotherapy in NSCLC.@*METHODS@#Patients with advanced non-small cell lung cancer who were hospitalized in The Affiliated Cancer Hospital of Nanjing Medical University from October 2018 to August 2019 were selected to receive anti-PD-1 (pembrolizumab, sintilimab or toripalimab) monotherapy or combination regimens. And were followed up until 10 December 2020, and the efficacy was evaluated according to RECIST1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were followed up for survival analysis. A clinical prediction model was constructed to analyze the predictive value of neutrophil-to-lymphocyte ratio (NLR) based on NLR data at three different time points: before treatment, 6 weeks after treatment and 12 weeks after treatment (0w, 6w and 12w), and the accuracy of the model was verified.@*RESULTS@#173 patients were finally included, all of whom received the above treatment regimen, were followed up for a median of 19.7 months. The objective response rate (ORR) was 27.7% (48/173), the disease control rate (DCR) was 89.6% (155/173), the median PFS was 8.3 months (7.491-9.109) and the median OS was 15.5 months (14.087-16.913). The chi-square test and logistic multi-factor analysis showed that NLR6w was associated with ORR and NLR12w was associated with ORR and DCR. Further Cox regression analysis showed that NLR6w and NLR12w affected PFS and NLR0w, NLR6w and NLR12w were associated with OS.@*CONCLUSIONS@#In patients with advanced non-small cell lung cancer, NLR values at different time points are valid predictors of response to immunotherapy, and NLR <3 is often associated with a good prognosis.

PD-1 blockade as a future treatment for colorectal cancer with microsatellite instability / Bloqueio do PD-1 como futuro tratamento do cancro colorretal com instabilidade de microssatélites

ABSTRACT Introduction: Colorectal cancer is the third most common cancer worldwide, with about 15% of these tumours related with microsatellite instability, which confers distinct characteristics to these tumours, both clinicopathological and in the response to treatments. In fact, the poor response to chemotherapy in these tumours has led to the investigation for new treatments, with immunotherapy being the most successful one to date. The focus of this review is to assess the response of microsatellite unstable colorectal cancer to PD-1 blockade, and the mechanisms behind that response. Methods: A PubMed research was conducted, resulting in the inclusion of 47 articles in this review. Results: Microsatellite instability results in a high neoantigen load, leading to a highly active immune microenvironment of the tumour, mainly due to T-cells. To counteract this, there is an upregulation of PD-1, acting as a "brake" for immune cells, facilitating tumour growth and metastasis. This upregulation makes these tumours great candidates for treatment with PD-1 blockade, as seen in many clinical trials, where the overall responses and progression free survival rates were higher than those observed in microsatellite stable tumours. Conclusion: With the importance of colorectal cancer with microsatellite instability new treatments are necessary. Therefore, PD-1 blockade is a promising treatment for colorectal cancer with microsatellite instability, with improvement in survival rates and a better prognosis for these patients.

RESUMO Introdução: O câncer colorretal é o terceiro mais comum em todo o mundo, com cerca de 15% desses tumores relacionados com instabilidade dos microssatélites, o que confere características distintas a esses tumores, tanto clínico patológicas quanto na resposta aos tratamentos. De fato, a fraca resposta à quimioterapia nesses tumores levou à investigação de novos tratamentos, sendo a imunoterapia a mais bem sucedida até o momento. O foco desta revisão é avaliar a resposta do câncer colorretal com microssatélites instáveis ao bloqueio do PD-1 e os mecanismos por trás dessa resposta. Métodos: Foi realizada uma pesquisa na base de dados PubMed, resultando na inclusão de 47 artigos nesta revisão. Resultados: A instabilidade de microssatélites resulta em uma alta carga de neoantígenos, levando a um microambiente imunológico altamente ativo do tumor, principalmente devido às células T. Para neutralizar isso, há uma maior expressão do PD-1, atuando como um "freio" para as células imunes, facilitando o crescimento do tumor e suas metástases. Essa expressão faz desses tumores grandes candidatos ao tratamento com bloqueio PD-1, como demonstrado em vários ensaios clínicos, onde as respostas globais e as taxas de sobrevivência livres de progressão foram maiores do que as observadas em tumores com microssatélites estáveis. Conclusão: Com a importância do câncer colorretal com instabilidade de microssatélites, novos tratamentos são necessários. Portanto, o bloqueio do PD-1 é um tratamento promissor para o câncer colorretal com instabilidade de microssatélites, com melhora nas taxas de sobrevivência e melhor prognóstico para esses pacientes.

Los ensayos clínicos en la ruta del cáncer a la cronicidad / Clinical trials in the way of cancer to a chronic disease

RESUMEN El cáncer es actualmente uno de los problemas de salud más importantes en la mayoría de los países occidentales. En Cuba, el cáncer es la segunda causa de muerte para todos los grupos de edad superada solo por las enfermedades cardiovasculares. En Matanzas, en los últimos años el cáncer ha mostrado una tendencia creciente con datos de incidencia y prevalencia por encima de la media del país. Por tales motivos realizamos este estudio con el objetivo de evaluar el impacto de la inmunoterapia como una alternativa terapéutica que mejora las funciones de supervivencia en pacientes con cáncer avanzado (AU).

SUMMARY Cancer is actually one of the most important health problems in the occidental countries. In Cuba, cancer is the second cause of death in all ages, under heart diseases. In Matanzas, in the last years cancer had showed and ascending growth on incidence and prevalence, over country media. That is wy, we make this study with the objective to evaluate the impact of inmunotherapy as a therapeutic alternative which increase the survival function in patients with advanced cancer (AU).

Efectividad de inducción de tolerancia inmune en niños con hemofilia A y aloanticuerpos neutralizantes / Immunotolerance induction effectivity in hemophilia A children and neutralizing alloantibodies

Resumen: Introducción: El desarrollo de aloanticuerpos neutralizantes anti-factor VIII en hemofilia A es la complicación más seria relacionada al tratamiento. La inducción de tolerancia inmune (ITI) o inmunotolerancia es el único tratamiento que erradica inhibidores, permitiendo utilizar nuevamente factor VIII para el tratamiento o profilaxis de eventos hemorrágicos. Objetivo: reportar la experiencia en niños sometidos a inmunotolerancia en la red pública del país. Pacientes y Método: Análisis retrospectivo y descriptivo de 13 niños con Hemofilia A severa e inhibidores persistentes de alto título, que recibieron ITI y seguimiento completo. Se utilizó concentrado de FVIII plasmático en dosis de 70-180 UI/Kg/diarias, definiendo éxito como la negativización del inhibidor y recu peración de la vida media del FVIII. Resultados expresados en media (rango). Resultados: En 13 pacientes se identificó el inhibidor, a una edad de 17,6 meses (2-48), tras 35,2 días (9-112) de exposición a FVIII. Once pacientes (84,6%) recuperaron la vida media del FVIII, tras 49,6 meses (26-70) de tratamiento. En los pacientes que respondieron, el título del inhibidor se negativizó en 7,3 meses (1-20). Conclusiones: En niños con hemofilia A e inhibidores persistentes de alto título, la ITI tiene un elevado éxito. Dado que el tiempo de respuesta es variable, la inmunotolerancia debe ser personalizada.

Abstract: Introduction: The development of anti-factor VIII neutralizing antibodies in hemophilia A is the most severe com plication related to treatment. Immune tolerance induction (ITI) is the only known treatment for eradicating inhibitors. A successful ITI allows using factor VIII (FVIII) again for the treatment or prophylaxis of hemorrhagic events. Objective: To report the experience of pediatric patients who underwent ITI in the country's public health care network. Patients and Method: Retrospective and descriptive analysis of 13 pediatric patients with severe Hemophilia A and high-titer inhibitors persis tence who underwent ITI and complete follow-up. Plasma-derived FVIII concentrate was used at 70 180 IU/kg/day doses. The success of the treatment is defined by achieving a negative titer and a half life recovery of the FVIII. The results were expressed in median (range). Results: In 13 patients, the inhibitor was identified at an average age of 17.6 months, after 35.2 days of exposure to the FVIII. 11 patients (84.6%) recovered the half-life of FVIII after 49.6 months of treatment. In the patients who responded to treatment, the inhibitor titer was negative at 6 months on average. Conclusions: ITI is the treatment of choice for patients with hemophilia A and inhibitors persistence. ITI must be perso nalized since the time response is variable in each patient.

LMP2-DC Vaccine Elicits Specific EBV-LMP2 Response to Effectively Improve Immunotherapy in Patients with Nasopharyngeal Cancer / 生物医学与环境科学（英文）

Objective@#To evaluate the safety and effectiveness of a vaccine based on latent membrane protein 2 (LMP2) modified dendritic cells (DCs) that boosts specific responses of cytotoxic T lymphocytes (CTLs) to LMP2 before and after intradermal injection in patients with nasopharyngeal carcinoma (NPC).@*Methods@#DCs were derived from peripheral blood monocytes of patients with NPC. We prepared LMP2-DCs infected by recombinant adenovirus vector expressing LMP2 (rAd-LMP2). NPC patients were immunized with 2 × 10 @*Results@#We demonstrated that DCs derived from monocytes displayed typical DC morphologies; the expression of LMP2 in the LMP2-DCs vaccine was confirmed by immunocytochemical assay. Twenty-nine patients with NPC were enrolled in this clinical trial. The LMP2-DCs vaccine was well tolerated in all of the patients. Boosted responses to LMP2 peptide sub-pools were observed in 18 of the 29 patients with NPC. The follow-up data of 29 immunized patients from April, 2010 to April 2015 indicated a five-year survival rate of 94.4% in responders and 45.5% in non-responders.@*Conclusion@#In this pilot study, we demonstrated that the LMP2-DCs vaccine is safe and effective in patients with NPC. Specific CTLs responses to LMP2 play a certain role in controlling and preventing the recurrence and metastasis of NPC, which warrants further clinical testing.

Clinical characteristics of primary extranodal versus nodal diffuse large B-Cell Lymphoma: A retrospective cohort study in a cancer center

Background The outcome of patients with primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) varies according to the primary site involved. Primary gastrointestinal, breast, bone, craniofacial, and testicular DLBCL are rare extranodal manifestations of DLBCL. Objective The objective of the study was to describe the clinical course of patients with PE-DLBCL disease in a referral cancer center. Results From 637 patients, 51 (8.77%) were considered as having PE-DLBCL (25 gastrointestinal, 12 craniofacial, 6 breast, 5 bone, and 3 with primary testicular DLBCL). Complete remission was higher in all PE-DLBCL sites (100% in testicular, 92.6% craniofacial, 83.3% breast, 80% bone, and 80% gastrointestinal) compared with 73.3% in nodal DLBCL. Although 2 cases with breast PE-DLBC relapsed, they achieved a complete response with chemotherapy. The overall survival at 5 years was 100%, 80%, 78%, 58%, 58%, and 62% for patients with primary breast, primary bone, gastrointestinal, primary craniofacial, primary testicular, and nodal DLBCL, respectively. Conclusions PE-DLBCLs constitute rare, primary sites of lymphoproliferative disorders in most cases, with localized disease and good prognosis. They require a combined chemoimmunotherapy with radiotherapy in most cases to improve local and systemic disease.

Pemphigus vulgaris

Abstract: Pemphigus vulgaris is a chronic autoimmune bullous dermatosis that results from the production of autoantibodies against desmogleins 1 and 3. It is the most frequent and most severe form of pemphigus, occurring universally, usually between 40 and 60 years of age. It usually begins with blisters and erosions on the oral mucosa, followed by lesions on other mucous membranes and flaccid blisters on the skin, which can be disseminated. There is a clinical variant, pemphigus vegetans, which is characterized by the presence of vegetating lesions in the large folds of the skin. Clinical suspicion can be confirmed by cytological examination, histopathological examination, and direct and indirect immunofluorescence tests. The treatment is performed with systemic corticosteroids, and immunosuppressive drugs may be associated, among them azathioprine and mycophenolate mofetil. More severe cases may benefit from corticosteroids in the form of intravenous pulse therapy, and recent studies have shown a beneficial effect of rituximab, an anti-CD20 immunobiological drug. It is a chronic disease with mortality around 10%, and septicemia is the main cause of death. Patients need long-term and multidisciplinary follow-up.

Inmunoterapia en cáncer: Perspectivas actuales, desafíos y nuevos horizontes / Immunotherapy in cancer. Current prospects, challenges and new horizons

La activación del sistema inmunológico en pacientes con cáncer ha sido un objetivo histórico en el campo de la oncología. En las últimas décadas, nuestro entendimiento de la respuesta inmunológica antitumoral ha promovido el desarrollo de novedosas estrategias terapéuticas dando como resultado un cambio de paradigma en el tratamiento del cáncer. La utilización de agentes bloqueantes de puntos de chequeo del sistema inmunológico como PD-1/PD-L1 y CTLA-4, de agonistas de moléculas co-estimuladoras como CD137 y OX-40 y la transferencia adoptiva de células T antitumorales modificadas genéticamente han generado importantes beneficios clínicos, reflejados en respuestas objetivas y durader as, en enfermos sin tratamientos convencionales disponibles. Sin embargo, un gran número de pacientes no responde a dichas terapias generando resistencia o sufriendo recaídas de la enfermedad debido a la aparición de circuitos inhibitorios o compensatorios. La combinación racional de estrategias terapéuticas permite eliminar mecanismos de resistencia, mientras que la identificación de biomarcadores predictivos facilita la selección de pacientes respondedores a dichos tratamientos. Recientes ensayos clínicos y estudios pre-clínicos permiten vislumbrar un escenario optimista con importantes desafíos en la implementación de estrategias de inmunoterapia en cáncer.

Recent under-standing of the mechanisms that control immune system homeostasis and orchestrate antitumor responses has prompted the development of novel immunotherapeutic modalities. These include antibodies that target immune checkpoints such as PD-1/PD-L1 and CTLA-4, agonistic antibodies of costimulatory molecules such as CD137 and OX-40 and the adoptive transfer of genetically-modified antitumor T cells. However, a large number of patients do not respond to these therapies and develop resistance as a result of activation of compensatory circuits. Rational combination of immunotherapeutic modalities will help overcome resistance and will increase the number of patients who will benefit from these treatments. Moreover, identification of predictive biomarkers will allow selection of patients responding to these treatments. Emerging clinical trials and pre-clinical studies have shown exciting results anticipating new horizons in the design and implementation of cancer immunotherapeutic modalities.

Immunostimulatory monoclonal antibodies for hepatocellular carcinoma therapy: Trends and perspectives

Hepatocellular carcinoma (HCC) is the second cause of cancer-related death in the world and is the main cause of death in cirrhotic patients. Unfortunately, the incidence of HCC has grown significantly in the last decade. Curative treatments such as surgery, liver transplantation or percutaneous ablation can only be applied in less than 30% of cases. The multikinase inhibitor sorafenib is the first line therapy for advanced HCC. Regorafenib is the standard of care for second-line patients. However, novel and more specific potent therapeutic approaches for advanced HCC are still needed. The liver constitutes a unique immunological microenvironment, although anti-tumor immunity seems to be feasible with the use of checkpoint inhibitors such as nivolumab. Efficacy may be further increased by combining checkpoint inhibitors or by applying loco-regional treatments. The success of immune checkpoint blockade has renewed interest in immunotherapy in HCC.

El hepatocarcinoma (HCC) es la segunda causa de muerte relacionada con el cáncer en el mundo y es la principal causa de muerte en pacientes cirróticos. Desafortunadamente, la incidencia de HCC ha crecido significativamente en la última década. Los tratamientos curativos como la cirugía, el trasplante de hígado o la ablación solo pueden aplicarse en menos del 30% de los casos. El sorafenib es el tratamiento de primera línea para el HCC avanzado, mientras que el regorafenib se reserva como segunda línea. Sin embargo, todavía son necesarios nuevos enfoques terapéuticos potentes y más específicos para el HCC avanzado. El hígado constituye un microambiente inmunológico único, aunque la inmunidad antitumoral parece ser factible mediante el uso de inhibidores de punto de control como nivolumab. La eficacia puede aumentarse adicionalmente combinando inhibidores de puntos de control inmunitario o aplicando tratamientos loco-regionales. En este sentido, el éxito del uso de anticuerpos monoclonales, que bloquean el control inmunitario, ha renovado el interés en la inmunoterapia para el HCC.

Current approaches to immunotherapy in noncolorectal gastrointestinal malignancies

Noncolorectal gastrointestinal (GI) malignancies are among the most frequently diagnosed cancers. Despite the undeniable progress in systemic treatments in recent decades, further improvements using cytotoxic chemotherapy seem unlikely. In this setting, recent discoveries regarding the mechanism underlying immune evasion have prompted the study of molecules capable of inducing strong antitumor responses. Thus, according to early data, immunotherapy is a very promising tool for the treatment of patients with GI malignancies. Noncolorectal GI cancers are a major public health problem worldwide. Traditional treatment options, such as chemotherapy, surgery, radiation therapy, monoclonal antibodies and antiangiogenic agents, have been the backbone of treatment for various stages of GI cancers, but overall mortality remains a major problem. Thus, there is a substantial unmet need for new drugs and therapies to further improve the outcomes of treatment for noncolorectal GI malignancies. "Next-generation" immunotherapy is emerging as an effective and promising treatment option in several types of cancers. Therefore, encouraged by this recent success, many clinical trials evaluating the efficacy of immune checkpoint inhibitors and other strategies in treating noncolorectal GI malignancies are ongoing. This review will summarize the current clinical progress of modern immunotherapy in the field of noncolorectal GI tumors.

Radiotherapy and immune response: the systemic effects of a local treatment

Technological developments have allowed improvements in radiotherapy delivery, with higher precision and better sparing of normal tissue. For many years, it has been well known that ionizing radiation has not only local action but also systemic effects by triggering many molecular signaling pathways. There is still a lack of knowledge of this issue. This review focuses on the current literature about the effects of ionizing radiation on the immune system, either suppressing or stimulating the host reactions against the tumor, and the factors that interact with these responses, such as the radiation dose and dose / fraction effects in the tumor microenvironment and vasculature. In addition, some implications of these effects in cancer treatment, mainly in combined strategies, are addressed from the perspective of their interactions with the more advanced technology currently available, such as heavy ion therapy and nanotechnology.